8-89981446-CAT-TAC

Variant names:

• chr8-89981446-CAT-TAC
• NM_002485.5:c.247_249delATGinsGTA
• NBN p.Met83Val

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PS1_Moderate

The NM_001024688.3(NBN):​c.1_3delATGinsGTA​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_001024688.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• Publications: 0 publications found

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 70 codons. Genomic position: 89980760. Lost 0.103 part of the original CDS.
• PS1: Another start lost variant in NM_001024688.3 (NBN) was described as [Likely_pathogenic] in ClinVar

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024688.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.247_249delATGinsGTA	p.Met83Val	missense	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1_3delATGinsGTA	p.Met1?	start_lost	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1_3delATGinsGTA	p.Met1?	start_lost	N/A	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.247_249delATGinsGTA	p.Met83Val	missense	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000409330.5	TSL:5	c.1_3delATGinsGTA	p.Met1?	start_lost	N/A	ENSP00000386924.1	A0A0C4DG07
	NBN	ENST00000517337.2	TSL:4	c.1_3delATGinsGTA	p.Met1?	start_lost	N/A	ENSP00000429971.2	A0A0C4DG07

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-90993674;